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Tumor-specific CD8 + T cells are exposed to persistent antigenic stimulation which induces a dysfunctional state called “exhaustion.” Though functioning to limit damage caused by immune response, T cell exhaustion leads to attenuated effector function whereby cytotoxic CD8 + T cells fail to control tumor progression in the late stage. This pathway is a dynamic process from activation to “progenitor exhaustion” through to “terminally exhaustion” with distinct properties. With the rapid development of immunotherapy via enhancing T cell function, new studies are dissecting the mechanisms and identifying specific biomarkers of dynamic differentiation during the process of exhaustion. Further, although immune checkpoint inhibitors (ICIs) have achieved great success in clinical practice, most patients still show limited efficacy to ICIs. The expansion and differentiation of progenitor exhausted T cells explained the success of ICIs while the depletion of the progenitor T cell pool and the transient effector function of terminally exhausted T cells accounted for the failure of immune monotherapy in the context of exorbitant tumor burden. Thus, combination strategies are urgent to be utilized based on the reduction of tumor burden or the expansion of the progenitor T cell pool. In this review, we aim to introduce the concept of homeostasis of the activated and exhausted status of CD8 + T cells in the tumor immune microenvironment, and present recent findings on dynamic differentiation process during T cell exhaustion and the implications for combination strategies in immune therapy.

Exosomes are representative extracellular vesicles (EV) derived from multivesicular endosomes (MVE) and have been described as new particles in the communication of neighborhood and/or distant cells by serving as vehicles for transfer between cells of membrane and cytosolic proteins, lipids, and nucleotides including micro (mi) RNAs. Exosomes from immune cells and tumor cells act in part as a regulator in tumor immunology. CD8+ T cells that show potent cytotoxic activity against tumor cells reside as an inactive naïve form in the T‐cell zone of secondary lymphoid organs. Once receiving tumor‐specific antigenic stimulation by dendritic cells (DC), CD8+ T cells are activated and differentiated into effector CTL. Subsequently, CTL circulate systemically, infiltrate into tumor lesions through the stromal neovasculature where mesenchymal stromal cells, for example, mesenchymal stem cells (MSC) and cancer‐associated fibroblasts (CAF), abundantly exist, destroy mesenchymal tumor stroma in an exosome‐mediated way, go into tumor parenchyma, and attack tumor cells by specific interaction. DC‐derived and regulatory T (Treg) cell‐derived exosomes, respectively, promote and inhibit CTL generation in this setting. In this review, we describe the roles of exosomes from immune cells and tumor cells on the regulation of tumor progression. Tumor progression is regulated by immune cell‐released exosomes. CD8+ T‐cell exosomes prevent tumor invasion and metastasis by depletion of mesenchymal tumor stromal cells.

Current influenza A virus (IAV) vaccines stimulate antibody responses that are directed against variable regions of the virus, and are therefore ineffective against divergent strains. As CD8+ T cells target the highly conserved, internal IAV proteins, they have the potential to increase heterosubtypic immunity. Early T‐cell priming events influence lasting memory, which is required for long‐term protection. However, the early responding, IAV‐specific cells are difficult to monitor because of their low frequencies. Here, we tracked the dissemination of endogenous IAV‐specific CD8+ T cells during the initial phases of the immune response following IAV infection. We exposed a significant population of recently activated, CD25+CD43+ IAV‐specific T cells that were not detected by tetramer staining. By tracking this population, we found that initial T‐cell priming occurred in the mediastinal lymph nodes, which gave rise to the most expansive IAV‐specific CD8+ T‐cell population. Subsequently, IAV‐specific CD8+ T cells dispersed to the bronchoalveolar lavage and blood, followed by spleen and liver, and finally to the lung. These data provide important insight into the priming and tissue dispersion of an endogenous CD8+ T‐cell response. Importantly, the CD25+CD43+ phenotype identifies an inclusive population of early responding CD8+ T cells, which may provide insight into TCR repertoire selection and expansion. A better understanding of this response is critical for designing improved vaccines that target CD8+ T cells. We tracked the dissemination of endogenous IAV‐specific CD8+ T cells during the initial phases of the immune response following IAV infection. We exposed a significant population of recently activated CD25+CD43+ IAV‐specific T cells that were not detected by tetramer staining. Identification of this subset provides a method to investigate factors that impact early T‐cell priming, which is critical for understanding how to generate durable memory to infections and vaccines.

Immunosuppressive therapy prevents graft rejection but increases the risk of non-melanoma skin cancer (NMSC), especially in elderly kidney transplant recipients (KTR). In this study, we separately investigated the differentiation of CD8 regulatory T cells (Tregs) and responder T cells (Tresps) between healthy KTR without NMSC, KTR developing NMSC within two years after the enrolment, and KTR with NMSC at the time of enrolment. Antigen-unexperienced CCR7 CD45RA CD31 recent thymic emigrant (RTE) cells differentiate CD45RA CD31 memory (CD31 memory) cells, resting mature naïve (MN) cells or direct proliferation into CD45RA CD31 memory (CD31 memory) cells, consisting of both CCR7 CD45RA central memory (CM) and CCR7 CD45RA effector memory (EM) cells. We found that both RTE Treg and Tresp differentiation CD31 memory Tregs/Tresps was age-independently increased in KTR, who developed NMSC during the follow-up period, causing abundant CM Treg/Tresp production, which may be crucial for cancer immunity. These changes favored a strongly increased CD8 Treg/Tresp ratio, suggesting this ratio as a reliable marker for NMSC development in KTR. However, with age, this differentiation was replaced by increased conversion of resting MN Tregs/Tresps into CM Tregs/Tresps, which exhausted for Tresps but not for Tregs. In KTR with already existing NMSC at enrolment, differentiation was maintained conversion and proliferation of resting MN Tregs/Tresps, which however increasingly exhausted with age, especially for Tresps. This resulted in a strong accumulation of terminally differentiated effector memory (TEMRA) Tresps in elderly individuals. Patients with NMSC recurrence showed increased proliferation of resting MN Tregs/Tresps into EM Tregs/Tresps, which tended to exhaust more rapidly, particularly for Tresps, than in patients without NMSC recurrence. In conclusion, we provide evidence that immunosuppressive therapy inhibits differentiation of CD8 Tregs more than that of CD8 Tresps, resulting in an exhausted Tresp profile, thus providing a possible therapeutic approach to improve poor cancer immunity in elderly KTR.

Under conditions of chronic antigen stimulation, such as persistent viral infection and cancer, CD8 T cells may diminish effector function, which has been termed \"exhaustion.\" Expression of inhibitory Receptors (iRs) is often regarded as a hallmark of \"exhaustion.\" Here we studied the expression of eight different iRs by CD8 T cells of healthy humans, including CTLA-4, PD1, TIM3, LAG3, 2B4, BTLA, CD160, and KLRG1. We show that many iRs are expressed upon activation, and with progressive differentiation to effector cells, even in absence of long-term (\"chronic\") antigenic stimulation. In particular, we evaluated the direct relationship between iR expression and functionality in CD8 T cells by using anti-CD3 and anti-CD28 stimulation to stimulate all cells and differentiation subsets. We observed a striking up-regulation of certain iRs following the cytokine production wave, in agreement with the notion that iRs function as a negative feedback mechanism. Intriguingly, we found no major impairment of cytokine production in cells positive for a broad array of iRs, as previously shown for PD1 in healthy donors. Rather, the expression of the various iRs strongly correlated with T cell differentiation or activation states, or both. Furthermore, we analyzed CD8 T cells from lymph nodes (LNs) of melanoma patients. Interestingly, we found altered iR expression and lower cytokine production by T cells from metastatic LNs, but also from non-metastatic LNs, likely due to mechanisms which are not related to exhaustion. Together, our data shows that expression of iRs per se does not mark dysfunctional cells, but is rather tightly linked to activation and differentiation. This study highlights the importance of considering the status of activation and differentiation for the study and the clinical monitoring of CD8 T cells.

Older adults often show signs of impaired CD8+ T‐cell immunity, reflected by weaker responses against new infections and vaccinations, and decreased protection against reinfection. This immune impairment is in part thought to be the consequence of a decrease in both T‐cell numbers and repertoire diversity. If this is indeed the case, a strategy to prevent infectious diseases in older adults could be the induction of protective memory responses through vaccination at a younger age. However, this requires that the induced immune responses are maintained until old age. It is therefore important to obtain insights into the long‐term maintenance of the antigen‐specific T‐cell repertoire. Here, we review the literature on the maintenance of antigen‐experienced CD8+ T‐cell repertoires against acute and chronic infections. We describe the complex interactions that play a role in shaping the memory T‐cell repertoire, and the effects of age, infection history, and T‐cell avidity. We discuss the implications of these findings for the development of new vaccination strategies to protect older adults. In this review, we aim to provide insight in the maintenance of antigen‐experienced CD8+ T‐cell clones during life. We describe what is already known on the effect of age on the virus‐specific T‐cell repertoire and discuss the contribution of infection history in shaping the repertoire. Insight in factors shaping the T‐cell repertoire will help to improve the protective memory response against infectious diseases in older adults.

Mounting an effective immune response relies critically on the coordinated interactions between adaptive and innate compartments. How and where immune cells from these different compartments interact is still poorly understood. Here, we demonstrate that the cross-talk between invariant natural killer T cells (iNKT) and CD8⁺ T cells in the spleen, essential for initiating productive immune responses, is biphasic and occurs at 2 distinct sites. Codelivery of antigen and adjuvant to antigen-presenting cells results in: 1) initial short-lived interactions (0 to 6 h), between CD8⁺ T cells, dendritic cells (DCs), and iNKT cells recruited outside the white pulp; 2) followed by long-lasting contacts (12 to 24 h) between iNKT cells, DCs, and CD8⁺ T cells occurring in a 3-way interaction profile within the white pulp. Both CXCR3 and CCR4 are essential to orchestrate this highly dynamic process and play nonredundant in T cell memory generation. While CXCR3 promotes memory T cells, CCR4 supports short-lived effector cell generation. We believe our work provides insights into the initiation of T cell responses in the spleen and their consequences for T cell differentiation.

T cells engineered to express chimeric-antigen receptors (CAR-T cells) can effectively control relapsed and refractory haematological malignancies in the clinic. However, the successes of CAR-T cell therapy have not been recapitulated in solid tumours due to a range of barriers such as immunosuppression, poor infiltration, and tumour heterogeneity. Numerous strategies are being developed to overcome these barriers, which include improving culture conditions and manufacturing protocols, implementing novel CAR designs, and novel approaches to engineering the T cell phenotype. In this review, we describe the various emerging strategies to improve CAR T cell therapy for solid tumours. We specifically focus on new strategies to modulate cell function and fate that have precipitated from the growing knowledge of transcriptional circuits driving T cell differentiation, with the ultimate goal of driving more productive anti-tumour T cell immunity. Evidence shows that enrichment of particular phenotypic subsets of T cells in the initial cell product correlates to improved therapeutic responses and clinical outcomes. Furthermore, T cell exhaustion and poor persistence are major factors limiting therapeutic efficacy. The latest preclinical work shows that targeting specific master regulators and transcription factors can overcome these key barriers, resulting in superior T cell therapeutic products. This can be achieved by targeting key transcriptional circuits promoting memory-like phenotypes or sustaining key effector functions within the hostile tumour microenvironment. Additional discussion points include emerging considerations for the field such as (i) targeting permutations of transcription factors, (ii) transient expression systems, (iii) tissue specificity, and (iv) expanding this strategy beyond CAR-T cell therapy and cancer.

For the development of new adenovirus (AdV)-based vectors, it is important to understand differences in immunogenicity. In a side-by-side in vitro analysis, we evaluated the effect of 40 AdV types covering human AdV (HAdV) species A through G on the expression of 11 activation markers and the secretion of 12 cytokines by AdV-transduced dendritic cells, and the effect on CD8 + T cell proliferation capacity. We found that the expression of activation markers and cytokines differed widely between the different HAdV types, and many types were able to significantly impair the proliferation capacity of CD8 + T cells. Univariate and multivariate regression analyses suggested an important role of type I interferons in mediating this suppression of CD8 + T cells, which we confirmed experimentally in a proliferation assay using a type I interferon receptor blocking antibody. Using Bayesian statistics, we calculated a prediction model that suggests HAdV types HAdV-C1, -D8, -B7, -F41, -D33, -C2, -A31, -B3 and -D65 as the most favorable candidates for vaccine vector development.

Protective lung tissue-resident memory CD8 + T cells (Trm) form after influenza A virus (IAV) infection. We show that IAV infection of mice generates CD69 + CD103 + and other memory CD8 + T cell populations in lung-draining mediastinal lymph nodes (mLNs) from circulating naive or memory CD8 + T cells. Repeated antigen exposure, mimicking seasonal IAV infections, generates quaternary memory (4M) CD8 + T cells that protect mLN from viral infection better than 1M CD8 + T cells. Better protection by 4M CD8 + T cells associates with enhanced granzyme A/B expression and stable maintenance of mLN CD69 + CD103 + 4M CD8 + T cells, vs the steady decline of CD69 + CD103 + 1M CD8 + T cells, paralleling the durability of protective CD69 + CD103 + 4M vs 1M in the lung after IAV infection. Coordinated upregulation in canonical Trm-associated genes occurs in circulating 4M vs 1M populations without the enrichment of canonical downregulated Trm genes. Thus, repeated antigen exposure arms circulating memory CD8 + T cells with enhanced capacity to form long-lived populations of Trm that enhance control of viral infections of the mLN.